Pemetrexed diacid and derivatives thereof act as a multi-targeted antifolate that strongly inhibit various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and the like, and have excellent anti-tumor activities. At present, the disodium salt, i.e., pemetrexed disodium has already been marketed in USA, the European Union, Canada, China, Japan etc., which is used for treating malignant pleural mesothelioma as a first-line drug, and treating non-small cell lung cancer as a first-line or second-line drug. In the treatment of malignant pleural mesothelioma, pemetrexed disodium is the only chemotherapeutic agent in the market currently. In the second-line treatment of non-small cell lung cancer, pemetrexed disodium has a comparative efficacy and low toxicities compared with the standard drug docetaxel, therefore, it is promising for pemetrexed disodium to become a new standard drug for the second-line treatment of non-small cell lung cancer. In addition, the clinical studies of pemetrexed disodium in the treatment of tumors of breast, bowel, pancreatic, head and neck, gastric, bladder and the like are ongoing, and the results are worthy of expectation.
Pemetrexed diacid is an essential precursor for the preparation of pemetrexed disodium, and the quality of pemetrexed diacid plays a key role in the preparation of pemetrexed disodium. Therefore, the physical and chemical properties of pemetrexed diacid have been recently studied in more detail. The polymorphism of pemetrexed diacid has drawn more attention, for example, U.S. patent No. US20080045711 disclosed seven crystalline forms of pemetrexed diacid, including two crystalline forms of hydrate (crystalline forms A, B), one crystalline form of DMSO solvate (crystalline form C), two crystalline forms of N,N-dimethyl formamide solvate (crystalline forms D, E), and two crystalline forms of anhydrate (crystalline forms F, G). Among these crystalline forms, solvents incorporated in crystalline forms C, D, and E have higher boiling points, wherein the boiling point is 189° for DMSO and 156° for N,N-dimethyl formamide. In the further preparation of pemetrexed disodium, the solvent with high boiling point may be introduced into final product, resulting in the increased burden of controlling organic residual in final product. Anhydrous crystalline forms F and G are obtained after drying at a higher temperature)(160˜200°) which may result in a certain extent of degradation of pemetrexed diacid, being adverse to the purity of product. Although the hydrate crystalline forms A and B overcome the disadvantages mentioned above, they have the following defects: the yield of crystalline A is quite low (about 40%) resulting in a low practical use; the time for preparing crystalline form B is quite long, wherein it takes about 18 hr only for the crystallizing step, which is unfavorable for the increase of the production efficiency. Thus, in order to overcome the shortcomings of crystalline forms of pemetrexed diacid in the prior art, we performed further studies on the polymorphism of pemetrexed diacid. Surprisingly, we have discovered several new crystalline forms of pemetrexed diacid. The methods for preparing these new crystalline forms are simple and practical, which are in favor of the further preparation of pemetrexed disodium.